Diabetic cardiomyopathy is a clinical condition characterized by ventricular dysfunction that develops in many diabetic patients in the absence of coronary artery disease or hypertension. Diabetic cardiomyopathy has become a major cause of diabetes-related morbidity and mortality. Despite the importance of this complication, the underlying mechanisms of diabetic cardiomyopathy are still incompletely understood. Based on four years of our investigation, our preliminary data, and evidence from literature, we propose that basal levels of autophagy are important for protecting cardiomyocytes against hyperglycemic damage and that a reduction of autophagy in diabetes contributes to the development of cardiomyopathy. Thus, the central hypothesis of this application is that AMPK activation protects cardiac structures and improves cardiac functions by increasing cardiac autophagy in diabetic heart. We propose the following specific aims to support or refute this hypothesis: Aim 1 is to establish the essential role of AMPK in maintaining mouse cardiac function and autophagy in diabetic hearts. Aim 2 is to the relative contributions of AMPK-dependent autophagy verse other metabolic effects of AMPK in the beneficial effects of AMPK in diabetic hearts. The last Aim is to elucidate the signaling pathways by which AMPK mediates autophagy in vivo and in cultured cardiac myocytes with or without high glucose exposure. This multidisciplinary, integrative, and translational approach to investigate the hypothesis that AMPK is critical in diabetic cardiomyopathy is technically and conceptually innovative. The proposed studies will provide new insights into how diabetes induces cardiomyopathy via the reduction of AMPK activity and a subsequent reduction of autophagic capacity and prove that specific modulation of autophagy such as stimulation of AMPK or up-regulation of Beclin 1 might be a novel approach to prevent this important complication of disease. We believe that the outcome of our investigation will have an immediate impact in providing cardioprotection in patients with diabetes, the most common metabolic disease affecting 21 million people in the United States. PUBLIC HEALTH RELEVANCE: The goal of this study is to elucidate the mechanisms underlying hyperglycemic damage to cardiac myocytes and to develop therapeutic strategies to improve cardiac function in diabetes. Multidisciplinary, integrative, and translational approaches will be employed to investigate the role of AMPK and autophage in diabetic cardiomyopathy. The proposed studies will provide new insights into how diabetes induces cardiomyopathy via the reduction of AMPK activity and a subsequent reduction of autophagic capacity and prove that specific modulation of autophagy such as stimulation of AMPK or up-regulation of Beclin 1 might be a novel approach to prevent this important complication of disease. It is our expectation that the outcomes of our investigation will have an immediate impact in providing cardioprotection in patients with diabetes. .